Karolina Pircs

Karolina Pircs
HCEMM · Semmelweis University

PhD

About

49
Publications
17,593
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1,802
Citations
Introduction
My research interest is to understand, using mouse models and aged patient-derived induced neurons obtained from fibroblasts, how alterations in autophagy contribute to healthy ageing and the pathophysiology of age-related, chronic neurodegenerative disorders such as Huntington’s disease.
Additional affiliations
November 2020 - present
HCEMM
Position
  • Group Leader
October 2020 - present
Semmelweis University
Position
  • Professor (Assistant)
November 2019 - present
Lund University
Position
  • Professor (Assistant)
Education
September 2009 - December 2013
Eötvös Loránd University
Field of study
  • Biology PhD
September 2004 - June 2009
Eötvös Loránd University
Field of study
  • Biology MSc

Publications

Publications (49)
Article
Full-text available
Altered microRNA (miRNA) expression is a common feature of Huntington’s disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts m...
Preprint
Altered microRNA (miRNA) expression is a common feature of Huntington's disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin (mHTT) binds to Ago2, a central component of miRNA biogenesis, and dis...
Article
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in aging humans. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibrobla...
Article
Full-text available
The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor ce...
Article
Full-text available
Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is...
Preprint
Full-text available
Understanding the pathophysiology of Parkinson’s disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinson’s disease...
Preprint
Full-text available
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD has remained challenging, as rodent and cellular models poorly recapitulate the disease. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent...
Article
Full-text available
Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for an inflammatory response, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9-based gene disruption o...
Article
Full-text available
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...
Preprint
Full-text available
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...
Preprint
Full-text available
the PDF can be download freely on pubmed. https://pubmed.ncbi.nlm.nih.gov/33634751/
Cover Page
Full-text available
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...
Preprint
Full-text available
The human forebrain has expanded in size and complexity compared to that of chimpanzee despite limited changes in protein-coding genes, suggesting that gene regulation is an important driver of brain evolution. Here we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells....
Preprint
Full-text available
Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for neuroinflammation, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9-based gene disruption of the e...
Article
Full-text available
Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In...
Article
Full-text available
DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. In this study, we use CRISPR-Cas9 technology to delete DNMT1, the DNA methyltransferase key for DNA methylation maintenance, in human neural progenitor cells (hNPCs). We observe that inactivation of DNMT1 in...
Article
Full-text available
Transposable elements (TEs) are dynamically expressed at high levels in multiple human tissues, but the function of TE-derived transcripts remains largely unknown. In this study, we identify numerous TE-derived microRNAs (miRNAs) by conducting Argonaute2 RNA immunoprecipitation followed by small RNA sequencing (AGO2 RIP-seq) on human brain tissue....
Article
Full-text available
Non-coding RNAs regulate many biological processes including neurogenesis. The brain-enriched miR-124 has been assigned as a key player of neuronal differentiation via its complex but little understood regulation of thousands of annotated targets. To systematically chart its regulatory functions, we used CRISPR/Cas9 gene editing to disrupt all six...
Preprint
Transposable elements (TEs) are dynamically expressed at high levels in multiple human tissues, but the function of TE-derived transcripts remains largely unknown. In this study, we identify numerous TE-derived microRNAs (miRNAs) by conducting Argonaute2 RNA Immunoprecipitation followed by small RNA sequencing (AGO2 RIP-seq) on human brain tissue....
Article
Full-text available
Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates, resulting in alterations in autophagy. However, the consequences of impaired autophagy for neuronal function remain poorly understood. In this study, we used cell culture and mouse models of huntingtin protein aggregation as well as post-mortem ma...
Article
Full-text available
Adult neurogenesis in the mammalian brain, including in humans, occurs throughout life in distinct brain regions. Alterations in adult neurogenesis is a common phenomenon in several different neurodegenerative disorders, which is likely to contribute to the pathophysiology of these disorders. This review summarizes novel concepts related to the int...
Article
Full-text available
Induced neurons (iNs), the product of somatic cells directly converted to neurons, are a way to obtain patient-derived neurons from tissue that is easily accessible. Through this route, mature neurons can be obtained in a matter of a few weeks. Here, we describe a straightforward and rapid one-step protocol to obtain iNs from dermal fibroblasts obt...
Article
Full-text available
Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the d...
Article
Full-text available
Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the d...
Article
Full-text available
Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult...
Article
During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here, we find that microRNA (miRNA) let-7 regulates radial migration by modulating autopha...
Article
Full-text available
The HOPS tethering complex facilitates autophagosome-lysosome fusion by binding to Syntaxin 17, the autophagosomal SNARE. Here we show that loss of the core HOPS complex subunit Vps16A enhances autophagosome formation and slows down Drosophila development. Mechanistically, Tor kinase is less active in Vps16A mutants likely due to impaired endocytic...
Article
Full-text available
HOPS is a tethering complex required for trafficking to the vacuole/lysosome in yeast. Specific interaction of HOPS with certain SNARE proteins ensures the fusion of appropriate vesicles. HOPS function is less well characterized in metazoans. Here we show that all six HOPS subunits (Vps11/CG32350, Vps18/Dor, Vps16A, Vps33A/Car, Vps39/CG7146 and Vps...
Article
Full-text available
Phagophore-derived autophagosomes deliver cytoplasmic material to lysosomes for degradation and reuse. Autophagy mediated by the incompletely characterized actions of Atg proteins is involved in numerous physiological and pathological settings including stress resistance, immunity, aging, cancer, and neurodegenerative diseases. Here we characterize...
Article
Full-text available
The Atg2-Atg18 complex acts in parallel to Atg8 and regulates Atg9 recycling from PAS during autophagy in yeast. Here we show that in Drosophila, both Atg9 and Atg18 are required for Atg8a puncta formation, unlike Atg2. Selective autophagic degradation of ubiquitinated proteins is mediated by Ref(2)P/p62. The transmembrane protein Atg9 accumulates...
Data
Quantification of experimental data. The number of individual animals quantified (n) is indicated for all genotypes. Note that in mosaic analyses, clone and control cell pairs were always evaluated from the same image, same tissue, same animal. P values≥0.05 (considered not statistically significant) are highlighted by a grey background. Please see...
Article
Full-text available
Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most...
Article
Full-text available
Two pathways are responsible for the majority of regulated protein catabolism in eukaryotic cells: the ubiquitin-proteasome system (UPS) and lysosomal self-degradation through autophagy. Both processes are necessary for cellular homeostasis by ensuring continuous turnover and quality control of most intracellular proteins. Recent studies establishe...
Article
Full-text available
During autophagy, phagophores capture portions of cytoplasm and form double-membrane autophagosomes to deliver cargo for lysosomal degradation. How autophagosomes gain competence to fuse with late endosomes and lysosomes is not known. In this paper, we show that Syntaxin17 is recruited to the outer membrane of autophagosomes to mediate fusion throu...
Article
Full-text available
Levels of the selective autophagy substrate p62 have been established in recent years as a specific readout for basal autophagic activity. Here we compared different experimental approaches for using this assay in Drosophila larvae. Similar to the more commonly used western blots, quantifying p62 dots in immunostained fat body cells of L3 stage lar...
Data
Endogenous p62 dots in Atg mutants. Loss of Atg2 (A), Atg7 (B), Atg8a (C), Atg13 (D), Atg18a (E) and Vps34 (F) all increase p62 aggregation. Scalebar in panel A equals 30 µm for all images. Genotypes are: (A) Atg2[EP3697]/Df(3L)BSC119]; (B) Atg7[d77]/Atg7[d14]; (C) Atg8a[d4]; (D) Atg13[Δ81]; (E) Atg18a[KG03090]/Df(3L)Exel6112]; (F) Vps34[Δm22]. (TI...
Data
p62-GFP aggregation in additional RNAi and overexpression lines. Knockdown of Atg7 (A), Atg8a (B), Atg9 (C), Atg14 (D), Atg18a (E), Pten (G), Tsc2 (H), RpS8(I), Atms (J) and expression of dominant-negative Vps34 (F) in p62-GFP expressing cell clones. Exposure times are indicated in the top right corner for each image. Scalebar in panel A equals 30...
Data
The effect of additional RNAi and overexpression lines on p62 aggregation. The effect of overexpressed dominant-negative Atg4 (B), dominant-negative Vps34 (G), wild-type Rheb (H), and knockdown of Atg2 (A), Atg7 (C), Atg8a (D), Atg9 (E), Atg14 (F), Atg16 (I, J), Atg18a (K, L), Pten (M, N) and Atms (O) on p62 aggregation. Scalebar in panel A equals...
Data
Knockdown of RpS8 or Atms inhibits starvation-induced mCherry-Atg8a and Lysotracker puncta formation. Silencing of RpS8 or Atms strongly interferes with starvation-induced mCherry-Atg8a dot formation (panels A and B, respectively) and blocks punctate Lysotracker staining (panels C and D, respectively). Scalebar in panel A equals 30 µm for all image...
Data
The effect of Atg16 RNAi lines on starvation-induced punctate Lysotracker staining in L3 and L2 larval stages. Both RNAi lines for Atg16 show a similar block of Lysotracker puncta formation in L3 (panels A and C), while the size of these dots is only reduced significantly by Atg16HMS in L2 (compare D to B; see also panel E for statistics). * indica...
Data
Overexpression of mCherry-Atg8a rescues the effect of Atg8a mutation or expression of dominant-negative Atg4 on p62 accumulation. Expression of mCherry-Atg8a reduces the size and number of p62 aggregates in Atg8a null mutants (A; see panel B for statistics). No accumulation of p62 dots is observed in fat body cells coexpressing mCherry-Atg8a and do...
Article
Full-text available
Autophagy delivers cytoplasmic material for lysosomal degradation in eukaryotic cells. Starvation induces high levels of autophagy to promote survival in the lack of nutrients. We compared genome-wide transcriptional profiles of fed and starved control, autophagy-deficient Atg7 and Atg1 null mutant Drosophila larvae to search for novel regulators o...